PROJECT SUMMARY/ABSTRACT The six-layered cerebral neocortex is assembled from diverse neuronal subtypes characterized by layer- dependent properties. To attain the laminar organization and neuronal diversity that support cortical circuit function, the full repertoire of distinct cell fates must be specified during neurogenesis. In the developing cortex, myriad subtypes of excitatory neurons arise from common neural progenitor cells (NPCs) that transition through distinct modes of cell production, sequentially specifying diverse cell types with a stereotyped temporal progression (deep-layer neurons ? upper-layer neurons ? astrocytes). Highlighting the significance of this process, disrupted cortical layering is found in cases of autism and genes expressed in layer-dependent patterns in the fetal human cortex have been strongly implicated in autism pathogenesis. The mechanisms underlying layer-dependent fate diversity and how their dysregulation can contribute to brain disorders remain largely unknown. However, sequential neurogenesis from common NPCs is at least a partially epigenetic process, wherein NPCs with the same genome inherit distinct transcriptional states appropriate for their stage in the neuro- gliogenic sequence. In preliminary studies, we found that polycomb repressive complex 2 (PRC2), a histone methyl-transferase complex that regulates transcriptional state dynamics via deposition of the repressive histone modification H3K27me3, plays cell type-specific roles in the sequential production of distinct neural fates from NPCs. In this application, we seek to understand the mechanisms by which PRC2 regulates corticogenesis. We hypothesize that PRC2 plays stage-dependent roles in sequential generation via the control of stage-dependent epigenetic programs and transcriptional states within NPCs. To test this hypothesis, we will first define the stage- specific requirement for PRC2 in sequential neurogenesis. Second, we will determine the effects of PRC2 on stage-dependent transcriptional states in cortical NPCs. Third, we will assess reconstitution of the epigenetic landscape following PRC2 re-expression. Histone methyl-transfer has emerged as a leading biological process altered in neurodevelopmental disorders. The successful completion of this study is expected to provide an understanding of histone regulation of corticogenesis, which is a prerequisite to realizing its potential to be pharmacologically targeted in brain disorders.